Alzheimer's disease (AD) is the most prevalent form of dementia. It is a neurodegenerative disease that is associated (though not exclusively) with aging. The disease is clinically characterized by a progressive loss of memory, cognition, reasoning and judgment that leads to an extreme mental deterioration and ultimately death. The disease is pathologically characterized by the deposition of extracellular plaques and the presence of neurofibrillary tangles. The plaques mainly consist of fibrillar aggregates of β-amyloid peptide (Aβ), which are products of the amyloid precursor protein (APP). APP is initially processed by β-secretase forming a secreted peptide and a membrane bound C99 fragment. The C99 fragment is subsequently processed by the proteolytic activity of γ-secretase. Multiple sites of proteolysis on the C99 fragment lead to the production of a range of smaller peptides (Aβ 37-42 amino acids). N-terminal truncations can also be found e.g., Aβ (4-42). For convenience, notations Aβ40 and Aβ42, as used herein, include these N-terminal truncated peptides. Upon secretion, the Aβ peptides initially form soluble aggregates which ultimately lead to the formation of insoluble deposits and plaques. Aβ42 is believed to be the most neurotoxic; the shorter peptides have less propensity to aggregate and form plaques. Aβ plaques in the brain are also associated with cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, multi infarct dementia, dementia pugilistica and Down's Syndrome.
γ-secretase is an association of four proteins: Aph1, nicastrin, presenilin and Pen-2 (review De Strooper, Neuron 38:9-12 (2003)). Subjects carrying particular mutations in one of these components, presenilin, show increased Aβ42/Aβ40 ratio. These mutations are correlated with early onset familial AD. Inhibition of γ-secretase resulting in the lowering of Aβ42 has been investigated by the pharmaceutical community, and numerous inhibitors have been found. See, e.g., Thompson et al. (Bioorg. Med. Chem. Lett. 2006, 16, 2357-63), Shaw et al. (Bioorg. Med. Chem. Lett. 2006, 17, 511-16) and Asberom et al. (Bioorg. Med. Chem. Lett. 2007, 15, 2219-2223). Inhibition of γ-secretase, though, is not without side-effects, some of which are due to the γ-secretase complex processing substrates other than C99, e.g., Notch. A more desirable approach is to modulate the proteolytic activity of the γ-secretase complex in a manner that lowers Aβ42 in favor of shorter peptides without significantly affecting the activity of γ-secretase on substrates such as Notch.
Compounds that have shown modulation of γ-secretase include certain non-steroidal, anti-inflammatory drugs (NSAIDs), for example Flurbiprofen, (Stock et al., Bioorg. Med. Chem. Lett. 2006, 16, 2219-2223). Other publications that disclose agents said to reduce Aβ42 through the modulation of γ-secretase include: WO 2004/074232, WO 2005/054193, Perreto et al., Journal of Medicinal Chemistry 2005, 48, 5705-20, WO 2005/108362, WO 2006/008558, WO 2006/021441, WO 2006/041874, WO 2006/045554, WO 2004/110350, WO 2006/043964, WO 2005/115990, EP 1847524, WO 2007/116228, WO 2007/110667, WO 2007/124394, EP 184752, EP 1849762, WO 2007/125364, WO 2009/086277 and others.